Serotonin 5-HT2A receptor involvement and Fos expression at the spinal level in vincristine-induced neuropathy in the rat.
We recently showed that peripheral and spinal 5-HT2A receptors (5-HT2AR) are involved in a rodent model of neuropathy induced by a nucleoside analogue reverse transcriptase inhibitor. In this paper, we show that 5-HT2AR are also involved in neuropathy induced by an anti-neoplasic drug, vincristine. Vincristine-treated rats (0.1mg/kg, daily i.p. administration for two 5-day cycles) developed thermal allodynia and mechanical hypersensitivity, which decreased in a dose-related manner after epidural injection a 5-HT2A receptor antagonist. Moreover, 5-HT2A-/- mice did not develop vincristine-induced neuropathy contrarily to their 5-HT2A+/+ littermates. In vincristine-treated rats, the number of nociceptive dorsal root ganglion cells expressing the 5-HT2AR was increased by 38%, and 5-HT2AR immunolabelling was enhanced in layers I-IV of the dorsal horn. At the EM level, a 76.3% increase in the density of 5-HT2AR immunopositive axon terminals within superficial layers of the dorsal horn was noted after vincristine treatment. Immunocytochemical study of Fos expression in vincristine-treated rats revealed a significant increase in the number of Fos-positive neurons not only in regions where nociceptive fibres terminate superficial (I-II) and deep layers (V-VI) of the spinal cord, but also in intermediate layers, suggesting that Abeta fibres could be involved in the spinal sensitization observed in this model. Double labelling experiments showed that Fos-positive neurons were endowed with 5-HT2AR immunolabelling in the dorsal horn of vincristine-treated rats. These data provide support to the idea that, in vincristine-induced neuropathy, 5-HT2AR are involved in the sensitization of peripheral nociceptors and spinal nociceptive processing.
Thibault
Karine
K
Neurobiologie des Signaux Intercellulaires, CNRS, UMR 7101, Université Pierre et Marie Curie-Paris 6, 7 Quai St. Bernard, 75252 Paris Cedex 05, France CNRS UMR 7637, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France INSERM UMR 677, Université Pierre et Marie Curie-Paris 6, Faculté de Médecine, site Pitié-Salpêtrière, 91 boulevard de l'Hôpital, 75634 Paris Cedex 13, France.
Van Steenwinckel
Juliette
J
Brisorgueil
Marie-Jeanne
MJ
Fischer
Jacqueline
J
Hamon
Michel
M
Calvino
Bernard
B
Conrath
Marie
M
D000818:Animals; D006358:Hot Temperature; D006941:Hyperesthesia / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D009437:Neuralgia / Q000139:chemically induced* / Q000378:metabolism*; D016761:Oncogene Proteins v-fos / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D013131:Spine / Q000503:physiopathology*; D014110:Touch; D014750:Vincristine
D016761:Oncogene Proteins v-fos; D044402:Receptor, Serotonin, 5-HT2A; D014750:Vincristine